Kv7.2/3 channels are voltage-gated potassium channels that modulate neuronal excitability in the central and peripheral nervous systems. Blockade of Kv7.2./7.3.channels, for example, by acetylcholine, increases neuronal excitability, whereas channel opening decreases it. Kv7 channels are expressed as homo or heterotetramers, composed of different subunit combinations. A deficiency in these channels is the underlying cause of a rare form of neonatal epilepsy, and polymorphisms in the Kv7.3 gene are associated with bipolar disorder based on linkage studies. The known Kv7 openers flupirtine (2-amino-6-[[(4-fluorophenyl)methyl]amino]-3-pyridinyl]-carbamic acid ethyl ester) and retigabine (N-(2-amino-4-(4-fluorobenzylamino)-phenyl)carbamic acid ethyl ester)) have shown numerous clinical applications, including, inter alia, epilepsy, pain, and cognitive function.
United States Patent Application 2007/0066612 relates to substituted pyrimidine derivatives which are alleged to be openers of the KCNQ family potassium ion channels, and, therefore, useful in the treatment of disorders and diseases being responsive to opening of the KCNQ family potassium ion channels, one such disease is epilepsy.
The present invention relates to dimethoxy-pyrimidine amide compounds of Formula I that exhibit activity as Kv7.2-5 channel openers.